Motives and considerations regarding PGT in couples carrying a structural chromosomal abnormality: a qualitative exploration.

PURPOSE: This study aims to describe the motives and considerations of couples carrying a structural chromosomal abnormality deciding on preimplantation genetic testing (PGT). METHODS: A qualitative exploratory study was conducted using semi-structured dyadic interviews with 13 couples (N = 26) carrying a structural chromosomal abnormality. All couples had an informative consultation in our PGT centre in the Netherlands. RESULTS: Almost all couples considered PGT or natural conception combined with prenatal diagnosis (PND) as the only two reproductive options. Among several considerations mentioned, the majority indicated that the wish to increase the chance of a successful pregnancy was the most important motive to opt for PGT. All couples who opted for PGT had first tried to conceive spontaneously and entered the PGT programme because of their adverse experiences during these attempts (infertility, recurrent miscarriage, termination of pregnancy, birth of an affected child). Couples that refrained from PGT were of advanced maternal age and expressed the long trajectory of PGT as the main reason to refrain. If conceiving spontaneously would not lead to an ongoing pregnancy, these couples also indicated that they would use PGT. CONCLUSION: This study shows that couples carrying a structural chromosomal abnormality consider PGT and spontaneous conception with PND as relevant reproductive options. They are looking for the option that is in their opinion the fastest way to establish a successful pregnancy. Information on the perceived pros and cons of PGT or spontaneous conception in these couples can help to optimize counselling and psychological support during the decision-making process.

Recurrent miscarriage in translocation carriers: no differences in clinical characteristics between couples who accept and couples who decline PGD.

STUDY QUESTION: Do clinical characteristics of recurrent miscarriage couples with a chromosomal abnormality and who opt for PGD differ from couples that decline PGD after extensive genetic counselling? SUMMARY ANSWER: No differences in clinical characteristics are identified between recurrent miscarriage couples carrying a structural chromosomal abnormality who opt for PGD compared with those that decline PGD after extensive genetic counselling. WHAT IS KNOWN ALREADY: Couples who have experienced two or more miscarriages (recurrent miscarriage) are at increased recurrence risk if one of the partners carries a structural chromosomal abnormality. PGD can be offered to avoid (another) miscarriage or pregnancy termination when (invasive) prenatal diagnosis shows an abnormal result. To date, no reports are available that describe reproductive decision-making after genetic counselling on PGD in these specific couples. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 294 couples carrying a structural chromosomal abnormality seeking genetic counselling on PGD between 1996 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were recurrent miscarriage couples carrying a structural chromosomal abnormality. They had been referred for genetic counselling to the only national licensed PGD centre. Clinical characteristics analysed included couple associated characteristics, characteristics concerning reproductive history and external characteristics such as type of physician that referred the couple for genetic counselling and the clinical geneticist performing the counselling on PGD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 294 couples referred for counselling on PGD, 26 were not accepted because they did not meet the criteria for IVF-PGD. The remaining cohort of 268 couples consisted of two-thirds female and one-third male carriers. Main PGD indications were reciprocal translocations (83.9%) and Robertsonian translocations (16.7%). Following genetic counselling, 76.9% of included couples chose PGD as their reproductive option, the others declined PGD. Reproductive choice is not influenced by sex of the translocation carrier (P = 0.499), type of chromosomal abnormality (P = 0.346), number of previous miscarriages (P = 0.882), history of termination of pregnancy (TOP) because of an unbalanced fetal karyotype (P = 0.800), referring physician (P = 0.208) or geneticist who performed the counselling (P = 0.410). LIMITATIONS, REASONS FOR CAUTION: This study only included recurrent miscarriage couples carrying a structural chromosomal abnormality, who were actually referred to a PGD clinic for genetic counselling. We lack information on couples who were not referred for PGD. Some of these patients may not have been informed on PGD at all, while others were not referred for counselling because they did not opt for PGD to start with. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that reproductive choices in couples with recurrent miscarriage on the basis of a structural chromosomal abnormality are not influenced by characteristics of the couple itself, nor by their obstetric history or external characteristics. These findings suggest that a couples' intrinsic attitude towards PGD treatment is a major factor influencing their reproductive choice. Future research will focus on these personal motives that seem to push reproductive decision-making following genetic counselling in a given direction.

Exercise related ventricular arrhythmias are related to cardiac fibrosis in hypertrophic cardiomyopathy mutation carriers.

AIMS: Hypertrophic cardiomyopathy (HCM) is a frequent cause of sudden cardiac death (SCD) due to exercise-related ventricular arrhythmias (ERVA); however the pathological substrate is uncertain. The aim was to determine the prevalence of ERVA and their relation with fibrosis as determined by cardiac magnetic resonance imaging (CMR) in carriers of an HCM causing mutation. METHODS: We studied the prevalence and origin of ERVA and related these with fibrosis on CMR in a population of 31 HCM mutation carriers. RESULTS: ERVA occurred in seven patients (23%) who all showed evidence of fibrosis (100% ERVA(+) vs. 58% ERVA(-), p = 0.04). No ventricular tachycardia or ventricular fibrillation occurred. In patients with ERVA, the extent of fibrosis was significantly larger (8 ± 4% vs. 3 ± 4%, p = 0.02). ERVA originated from areas with a high extent of fibrosis or regions directly adjacent to these areas. CONCLUSIONS: ERVA in HCM mutation carriers arose from the area of fibrosis detected by CMR; ERVA seems closely related to cardiac fibrosis. Fibrosis as detected by CMR should be evaluated as an additional risk factor to further delineate risk of SCD in carriers of an HCM causing mutation.

Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest doubleheterozygosity?

Background. With the improvement in genetic testing over time, double-heterozygous mutations are more often found by coincidence in families with hypertrophic cardiomyopathy (HCM). Double heterozygosity can be a cause of the wellknown clinical diversity within HCM families.Methods and results. We describe a family in which members carry either a single mutation or are double heterozygous for mutations in myosin heavy chain gene (MYH7) and cysteine and glycine-rich protein 3 (CSRP3). The described family emphasises the idea of a more severe clinical phenotype with double-heterozygous mutations. It also highlights the importance of cardiological screening where NT-proBNP may serve as an added diagnostic tool.Conclusion. With a more severe inexplicable phenotype of HCM within a family, one should consider the possibility of double-heterozygous mutations. This implies that in such families, even when one disease-causing mutation is found, all the family members still have an implication for cardiological screening parallel to extended genetic screening. (Neth Heart J 2009;17:458-63.).

Subtelomeric chromosome aberrations: still a lot to learn.

Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.

Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1).

Recently, the polyglutamine-binding protein 1 (PQBP1) gene was found to be mutated in five of 29 families studied with X-linked mental retardation (XLMR) linked to Xp. The reported mutations include duplications or deletions of AG dinucleotides in the fourth coding exon that resulted in shifts of the open reading frame. Three of the five families with mutations in this newly identified XLMR gene have been reported previously. We characterized the phenotypic and neuropsychological features in the two unpublished families with aberrations in PQBP1 and in a family reported 10 years ago. In total, seven patients diagnosed with aberrations in this gene were examined, including a newly identified patient at 18 months of age. Additionally, the features were compared to those reported in the literature of three other families, comprising MRXS3 (Sutherland-Haan syndrome) MRX55 and MRXS8 (Renpenning syndrome). Characteristics seen in these patients are microcephaly, lean body habitus, short stature, striking facial appearance with long narrow faces, upward slant of the eyes, malar hypoplasia, prognathism, high-arched palate and nasal speech. In addition, small testes and midline defects as anal atresia or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy of Fallot are seen in several patients. These observations contribute to the phenotypic knowledge of patients with PQBP1 mutations and make this XLMR syndrome well recognizable to clinicians.

Familial insertion (3;5)(q25.3;q22.1q31.3) with deletion or duplication of chromosome region 5q22.1-5q31.3 in ten unbalanced carriers.

We report on the clinical and cytogenetic data of a large family with an unbalanced insertion translocation (3;5)(q25.3;q22.1q31.3). Analysis of GTG-banded chromosomes demonstrated that unbalanced inheritance of a parental insertion translocation caused either a partial deletion or duplication 5q in this family. The derivative chromosomes were characterized further using microdissection and FISH with band-specific probes. The clinical picture of the proband with a partial deletion of chromosome 5 was characterized by moderate psychomotor retardation, mild facial dysmorphism, cleft palate, and single transverse crease. The family members with a partial duplication of chromosome 5 were borderline intelligent, had mild facial dysmorphism, a cardiac anomaly, and a high-pitched voice. The unbalanced carriers were compared with patients reported in the literature with a duplication or deletion of chromosome region 5q22.1 --> 5q31.3.

Intrachromosomal insertion translocation resulting in duplication of chromosome band Yq11.2 in two fertile brothers.

Chromosome analysis in a couple referred because of two spontaneous abortions showed a normal 46,XX karyotype in the 28-year-old female and an aberrant Y chromosome with an enlarged short arm in the 30-year-old male. Subsequent chromosome analysis showed that his 33-year-old brother was carrier of the same Y chromosome aberration. Further characterization of the aberrant Y chromosome with FISH using probes specific for chromosome bands Yp11.32, Yq11.2, the centromere and the subtelomeric region of the p-arm of the Y chromosome showed that chromosome band Yq11.2 was duplicated and inserted in the p-arm of the Y chromosome. Combining the results of the analysis of GTG-banded chromosomes and of the FISH analysis we conclude that both patients have a 46,X,ins dup(Y)(pter --> p11.23::q12 --> q11.1::p11.23 -->) karyotype. The clinical and cytogenetical findings are reported and discussed.

Maturational differences between vascular and bladder smooth muscle during ovine development.

Maturation rates of vascular and visceral smooth muscle (SM) during ovine development were compared by quantifying contractile protein, myosin heavy chain (MHC) isoform contents, and contractile properties of aortas and bladders from female fetal (n = 19) and postnatal (n = 21) sheep. Actin, myosin, and protein contents rose progressively throughout development in both tissues (P

Trisomy 7p: report of 2 patients and literature review.

Two patients with a trisomy 7p are reported. Both were assessed by facial dysmorphism and congenital anomalies. In one of the patients trisomy 7p was a de novo event, in the other patient unbalanced inheritance of a parental translocation caused trisomy 7p. Developmental delay was severe in both. Our 2 cases are compared with patients reported in literature.